Emerging literature indicates that mechanisms of aging and associated malignancies are intricately down-regulated both by calorie restriction regimens and calorie restriction mimetics, such as plant polyphenols. Among these natural polyphenols, one of the most studied is resveratrol, which is believed to modulate the activity of SIRT1, either directly, or indirectly via modulation of the activity of other enzymes and proteins such as the AMP-activated protein kinase (AMPK) (cf. D. Beher et al. Chem. Biol. Drug Des. 2009, 74, 619), the p70 ribosomal protein S6 kinase 1 (S6K1) (cf. S. M. Armour et al. Aging 2009, 1, 511) and integrin αv3 (cf. H. Y. Lin et al. FASEB J. 2006, 20, 1742). An increase in lifespan in saccharomyces cerevisiae through the administration of plant polyphenols has been described (cf. K. T. Howitz et al. Nature 2003, 425, 191), which could be related to the activation of sirtuins. Therefore, sirtuins constitute an important therapeutic target in many diseases associated with aging (cf. P. A. Cole Nature Chem. Biol. 2008, 4, 590; J. C. Milne, J. M. Denu Curr. Op. Chem. Biol. 2008, 12, 11).
As mentioned, one of the most studied plant polyphenol described to date is resveratrol, whose therapeutic potential is well documented through in vivo experiments (cf. J. A. Baur, D. A. Sinclair Nature Rev. Drug Discovery 2006, 5, 493). Thus, it has been described the ability of resveratrol to inhibit carcinogenesis in different stages (cf. M. Jang et al. Science 1997, 275, 218), all as chemoprevention by inhibiting cyclooxygenase and ornithine decarboxylase (cf. K. Subbaramaiah et al. J. Biol. Chem. 1998, 273, 21875), inhibition of angiogenesis (cf. S.-H. Tseng et al. Clin. Cancer Res., 2004, 10, 2190) and metastasis (cf. Y. Kimura, H. Okuda J. Nutr. 2001, 131, 1844), as well as induction of alterations in the cell cycle and apoptosis (cf. B. B. Aggarwal et al. Anticancer Res. 2004, 24, 2783). It also has been demonstrated that resveratrol prevents cardiovascular diseases (cf. H.-F. Li, S.-A. Chen, S.-N. Wu Cardiovasc. Res. 2000, 45, 1035; S. Bradamante, L. Barenghi, A. Villa Cardiovasc. Drug Rev. 2004, 22, 169) and has anti-inflammatory (cf. D.-S. Jang et al. Biochem. Pharmacol. 1999, 57, 705) and neuroprotective activity (cf. Y. K. Gupta, S. Briyal, G. Chaudhary Pharmacol. Biochem. Behav. 2002, 71, 245).
In this line, resveratrol has been observed to play a key role in the protection of neurons from Huntington's diseases (HD), Alzheimer Disease (AD), Parkinson's Disease (PD), ischemic brain injury, seizures and epilepsy (cf. T. S. Anekonda Brain Res. Rev. 2006, 52, 316).
Briefly, resveratrol was observed to protect neurons against polyQ toxicity in a mouse model of Huntington's disease (cf. J. A. Parker et al. Nat. Genet. 2005, 37, 349). In addition, in studies of Alzheimer Disease and Parkinson's disease (cf. A. Bedalov, J. A. Simon Science 2004, 305, 954), resveratrol treatment prior to axotomy also decreased axonal degeneration. Resveratrol was found to protect the degeneration of neurons from axotomy in Wallerian degeneration slow mice, a genetic model of slowed axonal degeneration (NAD levels decrease in degenerating axons, and preventing this axonal NAD decline protects axons from degeneration). In PC12 cells (model system for neuronal differentiation), resveratrol-protected cells from Aβ25-35 induced toxicity, attenuated apoptotic cell death, reduced changes in the mitochondrial membrane potential, inhibited the accumulation of intracellular reactive oxygen intermediates, and attenuated NF-κβ activation (cf. J. H. Jang, Y. J. Surh Free Radic. Biol. Med. 2003, 34, 1100).
In the same line, in rat hippocampal neurons, resveratrol inhibited voltage-activated K+ currents, suggesting that it may be useful for treating ischemic brain injury (cf. Z. B. Gao, G. Y. Hu. Brain Res. 2005, 1056, 68). Resveratrol was also found to provide protection against toxicity that was induced by sodium nitroprusside (SNP) and 3-morpho-linosydnonimine (SIN-1)-induced NO in mixed hippocampal cells from Sprague-Dawley rats (cf. S. Bastianetto, W. H. Zheng, R. Quirion Br. J. Pharmacol. 2000, 131, 711) and against kainic acid-induced excitotoxicity in the cortex and hippocampus of Wistar rats (cf. M. Virgili, A. Contestabile Neurosci. Lett. 2000, 281, 123). In an anoxia-reoxygenation model for stroke using Wistar rat cerebral mitochondria, resveratrol inhibited cytochrome C release, decreased the production of superoxide anion (O2−) and O2 consumption, and partly reversed the decline of the respiratory control ratio (cf. R. Zini et al. Life Sci. 2002, 71, 3091). After induced-stroke by the occlusion of common cortical arteries, resveratrol decreased delayed neuronal cell death and glial cell activation in Mongolian gerbils (cf. Q. Wang et al. Brain Res. 2002, 958, 439), prevented motor impairment, increased the levels of malodialdehyde, reduced glutathione, and decreased the volume of infarct in Wistar rats (cf. K. Sinha, G. Chaudhary, Y. K. Gupta Life Sci. 2002, 71, 655). Resveratrol also protected neurons, via antiplatelet aggregation, against vasodilating and antioxidant effects in Long-Evans rats (cf. S. S. Huang et al. Life Sci. 2001, 69, 1057). Resveratrol attenuated increased levels of malodialdehyde following kainic acid-induced seizure and epilepsy in albino Wistar rats (cf. Y. K. Gupta, S. Briyal, G. Chaudhary op. cit.).
These findings provide evidence that resveratrol and resveratrol analogues or calorie restriction mimetics can be useful in the protection from different types of neurological disorders.
Some of the properties listed above have also been observed in other trans-stilbenes of natural origin such as pterostilbene (cf. M. Tolomeo et al. Int. J. Chem. Cell Biol. 2005, 37, 1709), piceatannol (cf. L.-M. Hung et al. Free Radical Biol. Med. 2001, 30, 877; G. A. Potter et al. Brit. J. Cancer 2002, 86, 774) and isorhapontigenin (cf. Y. Liu, G. Liu Biochem. Pharmacol. 2004, 67, 777), as well as in derivatives or metabolites of resveratrol such as piceid, viniferin, resveratrol-3-sulfate, resveratrol-3-O-glucuronide and dihydro-resveratrol. In addition, several fluorinated and methoxylated analogues of these compounds have proved to be interesting candidates for the discovery of new chemopreventive and therapeutic treatments for cancer (cf. M. Roberti et al. J. Med. Chem. 2003, 46, 3546; S. Kim et al. J. Med. Chem. 2002, 45, 160).
Despite the therapeutic potential of resveratrol and other natural stilbenes, the results obtained from several pharmacokinetic studies indicate that circulating resveratrol is rapidly metabolized and has a low bioavailability (cf. J. A. Baur, D. A. Sinclair op. cit.).
Several resveratrol analogs have been described, such as 5-(6-hydroxynaphthalen-2-yl)benzene-1,3-diol (cf. F. Minutolo et al. J. Med. Chem. 2005, 48, 6783), (E)-2,2′-(5-(2-(pyridin-2-yl)-1,3-phenylene)bis(oxy)diacetic acid (cf. G. Chen et al. Chem. Pharm. Bull. 2005, 53, 1587), (E)-5-(3,5-dimethoxystyryl)-2-methoxyphenol (cf. M. Roberti et al. op. cit.), (E)-3-tert-butil-5-(3,5-dimethoxystyryl)benzene-1,2-diol (cf. R. Amorati et al. J. Org. Chem. 2004, 69, 7101), (E)-1,2-bis(3,5-dimethoxyphenyl)ethene (cf. S. Kim et al. op. cit.) and (Z)-5-(2-fluoro-2-(4-hydroxyphenyl)vinyl)benzene-1,3-diol (cf. S. Eddarir, Z. Abdelhadi, C. Rolando Tetrahedron Lett. 2001, 42, 9127). It also has been described the usefulness of nitrogenated heterocycles such as pyrroles and indoles as analogs of resveratrol (cf. F. P. Cossio et al. WO/2006/108864). Synthetic activators of Sir2 enzymes such as SRT1720 have been described as well, with therapeutic potential for treating diabetes (cf. J. C. Milne et al. Nature 2007, 450, 712). In general it can be said, however, that most synthetic analogues of resveratrol conserve the stilbene structure, along with the problems of bioavailability and pharmacokinetic profile associated with it.
In regard to inhibitors of sirtuins, synthetic molecules have also been described, such as splitomycin (cf. A. Bedalov et al. Proc. Natl. Acad. Sci. USA 2001, 98, 15113), sirtinol (cf. C. M. Grozinger et al. J. Biol. Chem. 2001, 276, 38837), cambinol (cf. B. Heitweg et al. Cancer Res. 2006, 66, 4368), dihydrocoumarin (cf. A. J. Olaharski et al. PLoS Genet. 2005, 1, e77), some indole derivatives (cf. A. D. Napper et al. J. Med. Chem. 2005, 48, 8045) or salermide (cf. E. Lara et al. Oncogene 2009, 28, 781). These molecules are able to inhibit sirtuins with IC50 values in the micromolar range, and have shown potent antitumor activity in vivo and in vitro, mainly by means of induction of apoptosis of tumor cells through induction of proapoptotic genes that are aberrantly repressed in cancer cells. However, the potencies of the inhibitors described to date can be improved significantly.